This invention relates to a novel process for the production of 4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonyl pyridinyl-dihydropyrazolo[4,3-d]pyrimidin-7-one derivatives, and, in particular, the anti-impotence drug, sildenafil and analogues thereof.
Sildenafil (5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), 
is the active ingredient in Viagra(trademark). The compound, which was originally disclosed in European patent application EP 463 756, has been found to be particularly useful in the treatment of inter alia male erectile dysfunction (see international patent application WO 94/28902).
Multi-step syntheses for the preparation of sildenafil are described in EP 463 756. An improved process for its production is described in a later application (European patent application EP 812 845), the final step of which involves an internal cyclisation under basic, neutral or acidic conditions.
We have now found that sildenafil and analogues thereof may be made via a novel process, as described hereinafter, which process has advantages over the processes described in the above-mentioned prior art documents.
According to a first aspect of the invention, there is provided a process for the production of compounds of general formula I: 
wherein
A represents CH or N;
R1 represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b and SO2NR11aR11b;
R2 and R4 independently represent lower alkyl;
R3 represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R5, R6, R7, R8, R9, R11a and R11b independently represent H or lower alkyl; R10a and R10b either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl, which process comprises the reaction of a compound of formula II, 
xe2x80x83wherein RX is a group substitutable by an aminopyrazole and A, R3 and R4 are as defined above, with a compound of general formula III, 
xe2x80x83wherein R1 and R2 are as defined above, which process is referred to hereinafter as xe2x80x9cthe process of the inventionxe2x80x9d.
The compounds of the general formulae I and III may be represented by either of the formulae I, IA and IB or IIIA or IIIB in the process according to the present invention. 
The term xe2x80x9carylxe2x80x9d, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl and the like.
Het groups may be fully saturated, partly unsaturated, wholly aromatic, partly aromatic and/or bicyclic in character. Het groups that may be mentioned include groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl, piperazinyl, thienyl and furanyl.
The point of attachment of any Het group may be via any atom in the ring system including (where appropriate) a heteroatom. Het groups may also be present in the N- or S-oxidised form.
The term xe2x80x9clower alkylxe2x80x9d (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, includes C1-6 alkyl (e.g. C1-4 alkyl). Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be substituted by one or more halo atoms.
As defined herein, the term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo.
Compounds of formulae I, IA and IB may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. The process of the invention thus also relates to the formation of stereoisomers of compounds of formulae I, IA and IB and mixtures thereof. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, crystallisation, chromatography over silica or, for example, via classical resolution with a homochiral acid salt). The formation of all stereoisomers is included within the scope of the invention.
Compounds of formula II may exhibit tautomerism. The use of all tautomeric forms of the compounds of formula II is included within the scope of the invention.
Preferred compounds of formulae I, IA and IB include those in which:
R1 represents C1-4 alkyl, which alkyl group is optionally interrupted by an oxygen atom, and/or is optionally terminated by a Het group (such as a pyridinyl group);
R2 represents C1-4 alkyl;
R3 represents C1-5 alkyl, which alkyl group is optionally interrupted by an oxygen atom;
R4 represents C1-3 alkyl.
More preferred compounds of formulae I, IA and IB include those in which:
R1 represents linear C1-3 alkyl, which alkyl group is optionally interrupted by an oxygen atom, or is optionally terminated by a 2-pyridinyl group (e.g. to form a 2-pyridinylmethyl group);
R2 represents linear C2-3 alkyl;
R3 represents linear or branched C2-4 alkyl, which alkyl group is optionally interrupted by an oxygen atom;
R4 represents C1-2 alkyl.
Particularly preferred compounds that may be formed in the process of the invention include sildenafil, and the following four compounds: 
Said compounds 1B, 1C, 1D and 1E are otherwise known as: 1B, (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one also known as 3-Ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, the compound of Example 118 of WO99/54333; 1C, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, the compound of Example 5 of WO98/49166; 1D, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, the compound of Example 4 of WO99/54333; and 1E, 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridyl sulphonyl}-4-ethylpiperazine, the compound of Example 8 of IB00/01457, exemplified hereinafter as Example 3.
By xe2x80x9cgroup substitutable by an aminopyrazole having structure IIIxe2x80x9d we include any group which, when present in the moiety xe2x80x94C(Rx)xe2x95x90NH of a compound of formula II, may undergo displacement by the amino group of an aminopyrazole such that a xe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94 linkage is thereby formed. In accordance with the process of the invention, which the skilled person will appreciate involves a xe2x80x9cone-potxe2x80x9d condensation/cyclisation reaction, the aminopyrazole that is reacted with the compound of formula II is a compound of formula III, IIIA or IIIB. Following the condensation reaction, the coupled intermediate undergoes cyclisation to form a compound of general formula I.
In this respect, preferred groups that Rx may represent include xe2x80x94NH2, xe2x80x94NHRa, xe2x80x94N(Rb)Rc, xe2x80x94SRd, xe2x80x94SH, xe2x80x94ORe wherein groups Rb to Re each independently represent the same groups that R1 as hereinbefore defined may represent (except that they do not represent H or alkoxy) as well as halo (e.g. chloro). Group Ra represents xe2x80x94OR1 or halo (e.g. chloro) wherein R1 is as hereinbefore defined. More preferred values of Rx include xe2x80x94NHRa, xe2x80x94N(Rb)Rc, and preferably xe2x80x94SRd, xe2x80x94SH and xe2x80x94ORe. Particularly preferred values of Rx are C1-4 alkoxy (e.g. ethoxy).
According to a further aspect of the invention, there is provided a process for the production of a compound of formula I, IA or IB, as hereinbefore defined, which process comprises the reaction of a compound of formula III, IIIA or IIIB (as appropriate), as hereinbefore defined, with a compound of formula II, as hereinbefore defined, provided that Rx does not represent xe2x80x94NH2, or, preferably, Rx does not represent xe2x80x94NH2, xe2x80x94NHRa or xe2x80x94N(Rb)Rc.
The process of the invention may be carried out in the presence of a suitable organic solvent system, which solvent system should not significantly react chemically with, or significantly give rise to stereochemical changes in, the reactants or product once formed, or significantly give rise to other side reactions. Preferred solvent systems include aromatic hydrocarbons (e.g. toluene or xylene) or chlorobenzene. Preferred solvent systems also include solvents of formula RxH, for example, solvents of formula ReOH (e.g. ethanol), wherein Rx and Re are as hereinbefore defined.
In the process of the invention, it may be preferable to add compounds of formulae III, IIIA or IIIB to the reaction mixture (prior to carrying out the reaction) in a suitable polar organic solvent such as ethyl acetate. Such a polar solvent may then be removed before the reaction is initiated.
The process of the invention may be carried at elevated temperature (e.g. up to the reflux temperature of the relevant solvent system, or higher if a pressurised system is employed). Clearly, appropriate reaction times and reaction temperatures depend upon the solvent system that is employed, as well as the reactants that are used and the compound that is to be formed, but these may be determined routinely by the skilled person.
We have found that compounds of formula II may be prepared, advantageously, by way of reaction of a compound of formula IV, 
wherein G represents a carboxylic acid group (xe2x80x94C(O)OH) or a derivative thereof, and A, R3 and R4 are as hereinbefore defined, with an appropriate reagent for converting the group G to a xe2x80x94C(Rx)xe2x95x90NH group, wherein Rx is as hereinbefore defined.
The term xe2x80x9cderivative of a carboxylic acid groupxe2x80x9d when used herein includes groups which are commonly derived from a carboxylic acid and/or groups that contain a central carbon atom (which carbon atom is attached to the phenyl or pyridyl ring in the compound of formula IV) that is at the same oxidation state as xe2x80x94C(O)OH. The term therefore includes groups such as xe2x80x94CN, xe2x80x94C(ORe)3, xe2x80x94C(O)NH2 or xe2x80x94C(xe2x95x90NORf)N(Re)2, wherein Rf represents H or lower alkyl and Re is as hereinbefore defined. G can also represent a 5- or 6-membered heterocyclic group containing at least two heteroatoms selected from O, S, N and mixtures thereof wherein said heterocyclic group is bonded by a carbon atom, a preferred heterocyclic group, as exemplified in preparation 4 herein, has the general formula xe2x80x94C(xe2x95x90NORg)N(Re) wherein the carbon is bonded to both N atoms and wherein Rg is bonded to the N of the xe2x80x94NRe group and wherein Rg is a xe2x80x94CH, or a xe2x80x94CH2xe2x80x94 group and wherein Re is as defined hereinbefore and is preferably H or lower alkyl or lower alkoxy.
Preferred compounds of formula IV include those in which, when A represents CH, then G does not represent xe2x80x94C(O)OH.
Procedures for the conversion of selected groups which G may represent to certain xe2x80x94C(Rx)xe2x95x90NH groups are known to those skilled in the art, and are described inter alia in: J. March, Advanced Organic Chemistry, 3rd Edition, Chapter 10, 371-374, John Wiley and Sons (1985); and Comprehensive Organic Functional Group Transformations, edited by A. Katritzky, O. Meth-Cohn, and C. Rees, 1st Edition, Volume 5, Sections 5.17 (page 653) and 5.19 (page 741), Pergamon Press (1995), the disclosures of which documents are hereby incorporated by reference. For example, compounds of formula II may be prepared by way of the following procedures.
1) For compounds of formula II in which Rx represents xe2x80x94ORe (wherein Re represents lower alkyl (optionally interrupted by O), alkylHet or alkylaryl, e.g. lower alkyl):
(a) a corresponding compound of formula IV in which G represents xe2x80x94CN may be reacted with an alcohol of formula VA,
Rxcex1OHxe2x80x83xe2x80x83VA
wherein Rxcex1 represents lower alkyl (optionally interrupted by O), alkylHet or alkylaryl (e.g. lower alkyl), and Het is as hereinbefore defined, in the presence of a suitable protic acid (e.g. HCl gas) and optionally in the presence of an appropriate solvent (e.g. diethyl ether, dioxan, benzene or chloroform). The skilled person will appreciate that such a reaction may be performed at low temperature (e.g. below 5xc2x0 C.);
(b) a corresponding compound of formula IV in which G represents xe2x80x94C(O)NH2 may be reacted with an appropriate alkylating agent of formula VB,
Rxcex1xe2x80x94Z1xe2x80x83xe2x80x83VB
wherein Z1 represents a leaving group such as halo, xe2x80x94OS(O)2ORxcex1, xe2x80x94OS(O)2CF3 or ORxcex12, and Rxcex1 is as hereinbefore defined, optionally in the presence of a suitable solvent (e.g. dichloromethane), followed by deprotonation of the resulting alkoxymethyleneiminium salt in the presence of a suitable base (e.g. NaOH or a tertiary amine such as triethylamine); or
(c) a corresponding compound of formula IV in which G represents xe2x80x94C(ORxcex1)3, wherein Rxcex1 is as hereinbefore defined, may be reacted with ammonia, or an N-protected derivative thereof, for example in the presence of a catalytic quantity of a suitable acid (e.g. a protic acid such as p-toluenesulfonic acid), and optionally in the presence of an appropriate solvent (e.g. dichloromethane).
2) For compounds of formula II in which Rx represents xe2x80x94ORe (wherein Re represents Het or aryl, e.g. phenyl), a corresponding compound of formula IV in which G represents xe2x80x94CN may be reacted with a compound of formula VC,
Rxcex2OHxe2x80x83xe2x80x83VC
wherein Rxcex2 represents Het or aryl (e.g. phenyl), and Het is as hereinbefore defined, for example in the presence of a suitable catalyst (e.g. a Lewis acid such as ZnCl2 and/or a protic acid such as HCl) and optionally in the presence of an appropriate solvent (e.g. dichloromethane).
3) For compounds of formula II in which Rx represents xe2x80x94NH2:
(a) a corresponding compound of formula IV in which G represents xe2x80x94CN may be reacted with hydrazine, hydroxylamine or O-lower alkyl hydroxylamine, followed by reduction of the resultant intermediate under standard conditions (e.g. palladium-catalysed hydrogenation); or
(b) a corresponding compound of formula IV in which G represents xe2x80x94C(xe2x95x90NORf)N(Re)2, wherein Rf is as hereinbefore defined, may be reduced under standard conditions (e.g. palladium-catalysed hydrogenation).
4) For compounds of formula II in which Rx represents xe2x80x94NH2, xe2x80x94NHRa or xe2x80x94N(Rb)Rc, a corresponding compound of formula IV in which G represents xe2x80x94CN may be reacted with a compound of formula VD,
xe2x80x83HN(R"khgr")(Rxcex4)xe2x80x83xe2x80x83VD
wherein R"khgr" and Rxcex4 independently represent H or Ra, and Ra is as hereinbefore defined, for example in the presence of a suitable catalyst (e.g. a copper(I) salt such as CuCl) and optionally in the presence of an appropriate solvent (e.g. dimethylsulfoxide or a lower alkyl alcohol such as methanol or ethanol).
5) For compounds of formula II in which Rx represents xe2x80x94SH:
(a) a corresponding compound of formula IV in which G represents xe2x80x94CN may be reacted with hydrogen sulfide, for example in the presence of a suitable base (e.g. a tertiary amine such as triethylamine) and optionally in the presence of an appropriate solvent (e.g. a lower alkyl alcohol such as ethanol); or
(b) a corresponding compound of formula IV in which G represents xe2x80x94C(O)NH2 may be reacted with a reagent that effects oxygen-sulfur exchange (e.g. P4S10 or Lawesson""s reagent), for example in the presence of an appropriate solvent (e.g. toluene).
6) For compounds of formula II in which Rx represents xe2x80x94SRd, a corresponding compound of formula IV in which G represents xe2x80x94CN may be reacted with a compound of formula VE,
RdSHxe2x80x83xe2x80x83VE
wherein Rd is as hereinbefore defined, for example in the presence of a suitable base (e.g. a tertiary amine such as triethylamine) and optionally in the presence of an appropriate solvent (e.g. a lower alkyl alcohol such as ethanol).
7) For compounds of formula II in which Rx represents halo (e.g. chloro), a corresponding compound of formula IV in which G represents xe2x80x94C(O)NH2 may be reacted with a suitable halogenating agent (e.g. a chlorinating agent such as PCl5 or S(O)Cl2), optionally in the presence of an appropriate solvent (e.g. benzene, CCl4, CHCl3 or dichloromethane).
Compounds of formula II may similarly be prepared from other compounds of formula II by reaction with a reagent that will convert one Rx group to another. In this respect, compounds of formula II may additionally be prepared by way of the following procedures.
I) For compounds of formula II in which Rx represents ORe (wherein Re represents lower alkyl, alkylHet or alkylaryl, e.g. lower alkyl), a corresponding compound of formula II in which Rx represents Cl may be reacted with a compound of formula VA, as hereinbefore defined, for example in the presence of an appropriate solvent (e.g. dichloromethane) and a suitable base (e.g. an alkali metal alkoxide such as sodium ethoxide, or a tertiary amine such as triethylamine).
II) For compounds of formula II in which Rx represents xe2x80x94NH2, xe2x80x94NHRa or xe2x80x94N(Rb)Rc, a corresponding compound of formula II in which Rx represents Cl, xe2x80x94SH, xe2x80x94SRd or xe2x80x94ORe, wherein Rd and Re are as hereinbefore defined, may be reacted with an appropriate compound of formula VD, as hereinbefore defined, or an acid (e.g. hydrogen chloride or CH3C(O)OH) addition salt thereof, for example optionally in the presence of an appropriate solvent (e.g. dichloromethane, ethanol, diethyl ether, dioxan, benzene or chloroform) and/or a suitable reaction promoter (for example: for reaction of compounds of formula II in which Rx represents xe2x80x94SH, a mercury(II) salt to act as a sulfide scavenger; and for reaction of compounds of formula II in which Rx represents xe2x80x94SRd, a pH buffer (e.g. sodium acetate/acetic acid)).
III) For compounds of formula II in which Rx represents xe2x80x94SRd, a corresponding compound of formula II in which Rx represents xe2x80x94SH may be reacted with a compound of formula VF,
Rdxe2x80x94Z2xe2x80x83xe2x80x83VF
wherein Z2 represents a leaving group such as halo (e.g. iodo), alkanesulfonate, perfluoroalkanesulfonate (e.g. trifluoromethane-sulfonate) or arenesulfonate (e.g. p-toluenesulfonate), and Rd is as hereinbefore defined, optionally in the presence of an appropriate solvent (e.g. dichloromethane or acetone) and/or a suitable base (e.g. a tertiary amine such as triethylamine).
Compounds of formula IV may be prepared via a variety of techniques. For example:
(a) Compounds of formula IV may be prepared by reaction of a compound of formula VI, 
xe2x80x83wherein L1 is a leaving group (e.g. halo) and A, G and R3 are as hereinbefore defined, with a compound of formula VII, 
wherein R4 is as hereinbefore defined. This reaction may be performed at, for example, low temperatures (e.g. between xe2x88x9210xc2x0 C. and room temperature), in the presence of an appropriate solvent (e.g. a C1-3 alcohol, ethyl acetate, dichloromethane, toluene or heptane), at least one equivalent of the compound of formula VII and, optionally, another suitable base (such as a base that does not react with or, if it does react, a base that further activates the sulfonyl chloride (for example: a tertiary amine such as triethylamine, N-ethyldiisopropylamine, 1,5-diazabicyclo[4.3.0]non-5-ene or 1,8-diazabicyclo[5.4.0]undec-7-ene; or a metal hydride, oxide, carbonate or bicarbonate)).
Compounds of formula VI are available using known techniques. For example, compounds of formula VI may be prepared from a corresponding compound of formula VIII, 
wherein A, G and R3 are as hereinbefore defined, for example using conventional methods for the introduction of a xe2x80x94SO2L1 group into an aromatic or heteroaromatic ring system, such as reaction of a compound of formula VIII, optionally in the presence of an appropriate solvent (e.g. dichloromethane), with a compound of formula L1SO3H and (optionally) a compound of formula SO(L1)2. When L1 is chloro, reaction may take place at between 0xc2x0 C. and room temperature in the presence of an excess of chlorosulfonic acid (optionally in conjunction with an excess of thionyl chloride), and optionally in an appropriate organic solvent (e.g. dichloromethane).
(b) Compounds of formula IV in which G represents xe2x80x94CN or xe2x80x94C(O)NH2 may be prepared by reaction of a compound of formula IX, 
xe2x80x83wherein Q represents xe2x80x94CN or xe2x80x94C(O)NH2, L2 represents a suitable leaving group and A and R4 are as hereinbefore defined, for example by reaction with a compound that will provide the group R3O (e.g. an alkoxide base). This route is preferred for the preparation of compounds of formula IV in which A represents N.
Suitable leaving groups L2 include standard groups known to those skilled in the art, such as optionally substituted arylsulfonyloxy groups (e.g. p-toluenesulfonyloxy), optionally substituted C1-4 alkanesulfonyloxy groups (e.g. methanesulfonyloxy, trifluoromethane-sulfonyloxy), halosulfonyloxy (e.g. fluorosulfonyloxy), halonium, diarylsulfonylamino (e.g. ditosyl), quaternary ammonium C1-4 alkylsulfonyloxy, C1-4 perfluoroalkanoyloxy (e.g. trifluoroacetyloxy), C1-4 alkanoyloxy (e.g. acetyloxy), aroyloxy (e.g. benzoyloxy), diazonium, oxonium or perchloryloxy groups.
More preferred values of L2 include a different lower alkoxy group to that which is to be replaced by the group R3O (e.g. methoxy, provided that R3 does not represent methyl) and, especially, halo (including bromo and, particularly, chloro).
The skilled person will appreciate that compounds that may serve to provide the group R3O include lower alkoxides of alkali metals (e.g. lithium, sodium, potassium), or of alkaline earth metals (e.g. magnesium, calcium). Preferred alkoxides include those of sodium and potassium.
Alternatively, the R3Oxe2x88x92 anion may be produced in situ by reaction of the relevant lower alkyl alcohol (or an alkali/alkaline earth metal alkoxide) with an auxiliary base, which should not compete with the relevant R3Oxe2x88x92 group in the nucleophilic substitution of L2 by being suitably sterically hindered. In this respect, suitable auxiliary bases may include a sterically hindered alkoxide or a secondary or tertiary amine.
Compounds of formula IX may be prepared by reaction of a compound of formula X, 
wherein A, Q and L2 are as hereinbefore defined with a compound of formula VII as hereinbefore defined, for example as described hereinbefore.
Compounds of formula X may be prepared by known techniques. For example compounds of formula X in which both L2 groups represent halo (e.g. chloro) may be prepared by reaction of a corresponding compound of formula XI,
wherein A and Q are as hereinbefore defined, with a suitable halogenating agent (e.g. thionyl chloride), for example at around 80 to 100xc2x0 C., optionally in the presence of a suitable solvent (e.g. dimethylformamide) and/or (optionally) an appropriate activating agent (e.g. dimethylformamide). The skilled person will appreciate that when an activating agent and a solvent are both employed, they may be either the same or different compounds.
Compounds of formula XI may be prepared by techniques known to those skilled in the art. For example, compounds of formula XI may be prepared by reacting a corresponding compound of formula XII,
wherein A and Q are as hereinbefore defined, with a sulfonating agent (e.g. oleum) under conditions known to those skilled in the art.
(c) Compounds of formula IV in which G represents xe2x80x94CN may alternatively be prepared by dehydration of a corresponding compound of formula IV in which G represents xe2x80x94C(O)NH2, under appropriate reaction conditions, for example at low temperature (e.g. at betweenxe2x88x925xc2x0 C. and room temperature (preferably at around 0xc2x0 C.)) in the presence of a suitable dehydrating agent (for example: P2O5; POCl3; PCl5; CCl4 and triphenylphosphine; trifluoroacetic anhydride and a suitable base (e.g. triethylamine or pyridine); or SOCl2) and an appropriate organic solvent (e.g. dichloromethane, toluene, chlorobenzene or heptane).
(d) Compounds of formula IV in which G represents xe2x80x94C(O)NH2 may be prepared from a corresponding compound of formula IV in which G represents xe2x80x94C(O)OH, for example by reaction with ammonia or a derivative thereof (e.g. ammonium acetate). The skilled person will appreciate that this reaction may preferably be carried out in the presence of an appropriate activating reagent (e.g. N,Nxe2x80x2-carbonyldiimidazole), in an appropriate solvent, e.g. ethyl acetate, dichloromethane or butan-2-one, resulting in the formation of an intermediate imidazolide (which may be isolated if desired), followed by reaction with e.g. ammonium acetate at between room and reflux temperature. Those skilled in the art will also appreciate that the activation of benzoic acid derivatives may also be accomplished with many other activating agents, for example as described in J. March, Advanced Organic Chemistry, 3rd Edition, Chapter 10, 371-374, John Wiley and Sons (1985).
(e) Compounds of formula IV in which G represents xe2x80x94C(O)OH may be prepared by known techniques. For example, such compounds may be prepared according to, or by analogy with, methods described in European patent application EP 812 845 (the disclosures in which document are hereby incorporated by reference). Compounds of formula IV in which G represents xe2x80x94C(O)OH may alternatively be prepared by reaction of a corresponding compound of formula XIII,
wherein A and L2 are as hereinbefore defined, with a compound that with provide the group R3O, for example under conditions as described hereinbefore for the preparation of compounds of formula IV.
Compounds of formula XIII may be prepared by known techniques, for example, according to, or by analogy with procedures described hereinbefore for the preparation of compounds of formula IX.
Other compounds of formula IV may be prepared from appropriate starting materials (which include inter alia compounds of formula IV), using techniques known to those skilled in the art and/or according to, or by analogy with procedures described hereinbefore for the preparation of compounds of formula II.
Compounds of formula IIIA, IIIB, VA, VB, VC, VD, VE, VF, VII, VIII, XII, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Compounds may be isolated from reaction mixtures using known techniques.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds defined herein may be converted to other substituents using techniques well known to those skilled in the art. For example, amino may be converted to amido, amido may be hydrolysed to amino, hydroxy may be converted to alkoxy, alkoxy may be hydrolysed to hydroxy etc.
It will be appreciated by those skilled in the art that, in the processes described above, the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.
Functional groups which it is desirable to protect thus include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl, allyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd edition, T W Greene and P G M Wutz, Wiley-Interscience (1999).
Persons skilled in the art will appreciate that, in order to obtain compounds of the formula II in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
Certain intermediates that are employed in the processes described herein are novel. According to the invention there is further provided: (a) compounds of formulae II as defined hereinbefore; and (b) compounds of formula IV as defined hereinbefore. Preferred compounds of formula II include those in which, when A represents CH, then Rx does not represent xe2x80x94NH2.
According to a further aspect of the invention there is provided compounds of formula II, as defined hereinbefore, in which Rx represents xe2x80x94SRd, xe2x80x94SH and xe2x80x94ORe (wherein Rd and Re are as hereinbefore defined).
The process of the invention may have the advantage that sildenafil and analogues thereof may be prepared from commercially-available starting materials in fewer steps than in processes described in the prior art, without concomitant losses in terms of yield of key intermediates and of final products.
Further, the process of the invention may have the advantage that sildenafil and analogues thereof may be prepared in less time, more conveniently, and at a lower cost, than when prepared in processes described in the prior art.
The invention is illustrated, but in no way limited, by the following examples.
All 1H NMR spectra were recorded using a Varian Unity 300 MHz machine.